Treatment-related acute myeloid leukemia and myelodyplastic syndrome (t-MDS/AML) are potential long- term complications in individuals after cancer therapy. The incidence of t-MDS/AML is increasing as more cancer patients are surviving longer following more intensive treatments. The role that genetic susceptibility and epidemiologic factors play in determining risk of developing t-MDS/AML has not been established. We hypothesize that specific polymorphisms involved in the metabolism of carcinogens (eg. GSTs, MPO, NQO1, CYPP2E1) or in DMA repair (eg. XRCC1, XRCC3, XPD), as well as epidemiological risk factors( e.g. smoking, occupational chemical exposures) modulate the risk of developing t-MDS/AML after treatment with alkylating agents and/or radiotherapy. This study builds upon two MDS and AML case-control studies conducted by Dr. Strom. We propose to conduct a case-comparison study to compare 300 t-MDS/AML patients already enrolled in these studies to 600 patients who have not developed second malignancies and are matched to our cases on first primary cancer type and treatment along with age, sex, and ethnicity. The large patient population at U.T. MD Anderson Cancer Center provides the opportunity to recruit and characterize the patients necessary to make this study possible. Integrating information on inherited genetic polymorphisms, clinical characteristics, family history, demographic and lifestyle factors will provide a unique opportunity for the identification of factors involved in t-MDS/AML pathogenesis. Increasing our understanding of factors that modulate risk will allow clinicians to individualize treatments to minimize long-term risk of t-MDS/AML while still providing effective cancer treatment. We believe that this study will provide future hypotheses for research into treatment- related malignancies, and may lead to eventual improvements in cancer survivorship. [unreadable] [unreadable] [unreadable]